Dual Ferroptosis-Inhibitory and Antifungal Therapy for Fungal Keratitis Using a Defect-Adhesive Thermoresponsive Hydrogel

Fungal keratitis is a major cause of corneal blindness and remains difficult to treat due to poor drug retention, frequent dosing, and inadequate modulation of pathogenic mechanisms. Current therapies largely focus on antifungal efficacy while neglecting inflammation-, fibrosis-, and cell death–related pathways. Here, ferroptosis is identified as a critical pathogenic target, and a synergistic therapeutic strategy is developed using a thermosensitive in situ-forming hydrogel composed of poloxamer and hyaluronic acid, enabling the co-delivery of a ferroptosis inhibitor (ferrostatin-1, Fer-1) and the antifungal agent (voriconazole, VOR), termed PX/HA/Fer-1/VOR hydrogel. Upon administration, the hydrogel exhibits lens-like adhesion to corneal defects, forming a localized drug reservoir that significantly enhances corneal retention and prolongs drug residence time by at least 90 min. In vitro studies demonstrate enhanced antifungal activity, while in vivo fungal keratitis models show superior therapeutic efficacy compared with conventional voriconazole eye drops administered six times daily. Notably, a single daily application effectively suppresses inflammation, reduces corneal fibrosis and scarring, and promotes recovery of visual function. Mechanistically, the composite hydrogel exerts synergistic effects through zinc ion chelation–mediated antifungal activity, inhibition of ferroptosis, and attenuation of fibrosis. This multifunctional hydrogel platform offers a promising therapeutic strategy for fungal keratitis.